We have previously identified 12 surface antigens whose differential expression represented the signature of B‐cell chronic lymphocytic leukemia (B‐CLL) subsets with different prognosis. In the present study, expression data for these antigens, as determined in 137 B‐CLL cases, all with survivals, were utilized to devise a comprehensive immunophenotypic scoring system of prognostic relevance for B‐CLL patients. In particular, univariate z score was employed to identify the markers with greater prognostic impact, while maximally selected log‐rank statistics were chosen to define the optimal cut‐off points capable to split patients into two groups with different survivals. A weighted immunophenotypic scoring system was developed by integrating results from these analyses. Six antigens were selected: three positive prognosticators (CD62L, CD54, CD49c) and three negative prognosticators (CD49d, CD38, CD79b), with cut‐off values ranging from 30% to 50% of positive cells. By weighing the expression of each marker according to its statistical power, a complete scoring system, with point values comprised between 0 (complete absence of phenotypic conditions associated with good prognosis) and 9 (all the phenotypic conditions associated with good prognosis fulfilled), allowed to split the whole set of B‐CLL patients, into three distinctive prognostic groups (P = 4.78 × 10⁻¹¹) with high‐ (score 0–3), intermediate‐ (score 4–6), and low‐ (score 7–9) risk of death. The three risk groups showed different distribution of cases as for Rai's stages, IgV_H mutations, and ZAP‐70 expression. The proposed immunophenotypic scoring system may be an additional useful tool in routine diagnostic/prognostic procedures for B‐CLL. J. Cell. Physiol. 207: 354–363, 2006. © 2005 Wiley‐Liss, Inc.